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WO2003066052A1 - Agent anticancereux renfermant du nitro-imidazole et un inhibiteur de la topoisomerase comme ingredients actifs - Google Patents

Agent anticancereux renfermant du nitro-imidazole et un inhibiteur de la topoisomerase comme ingredients actifs Download PDF

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Publication number
WO2003066052A1
WO2003066052A1 PCT/KR2003/000276 KR0300276W WO03066052A1 WO 2003066052 A1 WO2003066052 A1 WO 2003066052A1 KR 0300276 W KR0300276 W KR 0300276W WO 03066052 A1 WO03066052 A1 WO 03066052A1
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Prior art keywords
doxorubicin
under
pimonidazole
state
cells
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PCT/KR2003/000276
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English (en)
Inventor
Jong-Won Lee
Sun-Ha Lim
Hong-Tae Kim
Hun-Suk Suh
Sung-Hwan Park
Yang-Il Kim
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Hypoxi Co Ltd
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Hypoxi Co Ltd
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Priority to AU2003208037A priority Critical patent/AU2003208037A1/en
Publication of WO2003066052A1 publication Critical patent/WO2003066052A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to an anticancer agent comprising active ingredients of nitroimidazole compound and topoisomerase inhibitor, more specifically, to an anticancer agent comprising active ingredients of nitroimidazole compound such as pimonidazole, misonidazole, etanidazole and ornidazole, and a topoisomerase inhibitor such as doxorubicin, mitomycin C, camptothecin, novobiocin, epirubicin, dactinomycin and etoposide, and their pharmaceutically acceptable carriers.
  • nitroimidazole compound such as pimonidazole, misonidazole, etanidazole and ornidazole
  • a topoisomerase inhibitor such as doxorubicin, mitomycin C, camptothecin, novobiocin, epirubicin, dactinomycin and etoposide, and their pharmaceutically acceptable carriers.
  • Anticancer agent is the general term for those drugs that act upon various metabolic pathways of a cancer cell, thereby having cytotoxic or cytostatic effects on the cancer cell. Anticancer agents developed so far can be classified into metabolic antagonist, vegetable alkaloid, topoisomerase inhibitor, al ylating agent, anticancer antibiotic, hormonal agent and the others, depending on their mode of action and chemical structure. Anticancer agents have a variety of intracellular targets: for example, some agents block DNA replication, transcription and translation, and others inhibit the action of protein' s essential for cell survival. These activities on intracellular targets, lead the cells to death by way of necrosis or apoptosis.
  • Topoisomerase is an enzyme essential for changing the topology of DNA during DNA replication, which is classified into type I-A, type I-B and type II.
  • Topoisomerase type I- A includes bacterial ⁇ protein, topoisomerase III and reverse DNA gyrase
  • topoisomerase type I-B includes eukaryotic topoisomerase
  • topoisomerase type II includes prokaryotic DNA gyrase, topoisomerase IV and mammalian topoisomerase Il ⁇ and II ⁇ .
  • Topoisomerase inhibitors for anticancer agents act specifically upon the above topoisomerase species.
  • topoisomerase II inhibitor includes anthracyclines such as doxorubicin, quinolones such as ofloxacin, and flavones
  • topoisomerase I-B inhibitor includes camptothecin
  • actinomycin D act upon both types of topoisomerase.
  • topoisomerase inhibitors lead the cell to death by way of inhibiting the activity of topoisomerase which is expressed much in cancer cell relative to normal cell. Therefore, it has been known that they cause less harmful effects and possess much more potent anticancer activities than any other anticancer agents.
  • Some types of cancers can be completely cured over 90% if they are diagnosed early and treated properly, while solid cancers, such as lung cancer, liver cancer and rectum cancer, although various anticancer agents are clinically used, are hard to be cured.
  • Major anticancer therapy includes surgical extirpation, radiotherapy and chemotherapy using anticancer agents. Among them, though the chemotherapy with oral administration or injection of anticancer agent can be easily performed, while not imposing a heavy burden to the patient and not giving fear and discomfort. The chemotherapy is, however, proven to be less satisfactory in the senses that it provides almost no or about 1% therapeutic effect for solid cancers, or even propagates the cancer cell finally to reduce the life span of the patient.
  • an anticancer agent comprising a topoisomerase inhibitor, though it maintains the survival of caner cells under the state of hypoxia, can induce cell death regardless of oxygen condition if co-administered with nitroimidazole compounds.
  • a primary object of the present invention is, therefore, to provide an anticancer agent comprising active ingredients of nitroimidazole compound and topoisomerase inhibitor.
  • Figures la and lb are graphs showing cell survival rates depending on the changes of doxorubicin concentration, under normoxic and hypoxic condition, respectively.
  • Figures 2a and 2b are graphs showing the concentrations of glucose in cell culture depending on the changes of doxorubicin concentration, under normoxic and hypoxic condition, respectively.
  • Figures 3a and 3b are graphs showing the concentrations of lactose in cell culture depending on the changes of doxorubicin concentration, under normoxic and hypoxic condition, respectively.
  • Figures 4a, 4b and 4c, and 5a, 5b and 5c are photographs of electrophoresis showing DNA fragmentation patterns depending on the changes of doxorubicin concentration, under normoxic and hypoxic condition, respectively.
  • Figures 6a and 6b are graphs showing cell survival rates depending on the changes of pimonidazole concentration, under normoxic and hypoxic condition, respectively.
  • Figures 7a and 7b are graphs showing the concentrations of glucose in cell culture depending on the changes of pimonidazole concentration, under normoxic and hypoxic condition, respectively.
  • Figures 8a and 8b are graphs showing the concentrations of lactose in cell culture depending on the changes of pimonidazole concentration, under normoxic and hypoxic condition, respectively.
  • Figures 9a and 9b are graphs showing cell survival rates depending on the changes of pimonidazole and doxorubicin concentrations, under normoxic and hypoxic condition, respectively.
  • Figures 10a and 10b are graphs showing the concentrations of glucose in cell culture depending on the changes of pimonidazole and doxorubicin concentrations, under normoxic and hypoxic condition, respectively.
  • Figures 11a and lib are graphs showing the concentrations of lactose in cell culture depending on the changes of pimonidazole and doxorubicin concentrations, under normoxic and hypoxic condition, respectively.
  • Figures 12a, 12b and 12c, and 13a, 13b and 13c are photographs of electrophoresis showing DNA fragmentation patterns depending on the changes of pimonidazole and doxorubicin concentrations, under normoxic and hypoxic condition, respectively.
  • the anticancer agent of the present invention comprises active ingredients of nitroimidazole compound and topoisomerase inhibitor, and their pharmaceutically acceptable carriers.
  • 100 to 1000 ug/mL of nitroimidazole and 0.1 to 100 ug/mL of topoisomerase inhibitor are effective for 2.5 x 10 5 cell/mL of cancer cell, where the nitroimidazole compound can be pimonidazole, misonidazole, etanidazole or ornidazole and the topoisomerase inhibitor can be doxorubicin, mitomycin C, camptothecin, novobiocin, epirubicin, dactinomycin or etoposide, respectively.
  • the present invention is further illustrated in more detail as follows.
  • topoisomerase inhibitor into solid cancer even cause to the propagation of the cancer. Under the circumstance, they made every efforts to improve its anticancer activity under the state of hypoxia, and found that it can efficaciously induce cell death under the states of both normoxia and hypoxia if co- administered with nitroimidazole which had been considered that it does not cause cell damage under normoxic condition and induce cell death by generating free radical under hypoxic condition.
  • the anticancer agent of the invention comprising nitroimidazole and topoisomerase inhibitor induces cell death by the activity of topoisomerase inhibitor under the state of normoxia as well as by the activity of nitroimidazole under the state of hypoxia. Accordingly, the anticancer agent can be practically applied for the treatment of almost all kinds of cancer, inter alia , solid cancer creating the state of hypoxia.
  • Example 1 Effects of topoisomerase inhibitor on survival and metabolism of cells
  • doxorubicin an anticancer agent acting as a topoisomerase inhibitor, has an effect on the survival and metabolism of cells.
  • doxorubicin an anticancer agent acting as a topoisomerase inhibitor
  • HepG2 human hepatocelluar carcinoma cell line, ATCC HB 8065
  • MEM minimum essential medium
  • FBS fetal bovine serum
  • Example 1-2 Effects of doxorubicin on survival and metabolism of cells
  • the glucose consumption and the production and consumption of lactic acid were measured by the concentrations of glucose and lactic acid in a culture solution, respectively:
  • Cells attached to 60mm plate as in Example 1-2-1 were treated with a certain concentration of doxorubicin under the state of normoxia or hypoxia, and cultures were collected from the culture solution every 24 hours and kept freezing at the temperature of -70°C.
  • the concentration of glucose was measured by using a reagent for AsanTech GLU II autoanalyzer (Hitachi 747, Hitachi, Japan) .
  • Figures 2a and 2b are graphs showing the concentrations of glucose in cell culture depending on the changes of doxorubicin concentration under the state of normoxia and hypoxia, respectively. As shown in Figures 2a and 2b, it was found that: under the state of normoxia, as the concentration of doxorubicin increased, the survival rate of cells was decreased and the concentration of glucose was lowered; under the state of hypoxia, the concentration of glucose was lowered rapidly after 24 hours, regardless of the concentration of doxorubicin.
  • Figures 3a and 3b are the graphs showing the concentrations of lactic acid in cell culture depending on the changes of doxorubicin concentration under the state of normoxia and hypoxia, respectively.
  • the concentrations of lactic acid, at the concentration range of doxorubicin of 0.01 and O.l ⁇ g/mL increased to the elapsed time of 24hours and decreased after 24hours, and the concentration of lactic acid, at the other concentration ranges, increased a little consistently; and, under the state of hypoxia, the produced lactic acid, in all the cases, was hardly consumed until 24hours. From the results of Figures la, lb, 2a, 2b, 3a and 3b, it could be concluded that:
  • Example 1-3 Cell death by doxorubicin
  • doxorubicin an anticancer agent acting as a topoisomerase inhibitor, on cell death under the state of normoxia and hypoxia, DNA fragmentation, a major phenomenon of apoptosis was examined, respectively:
  • Cells attached to 60mm plate were treated by 0 (see: Figures 4a and 5a), 0.1 (see: Figures 4b and 5b) and l ⁇ g/mL (see: Figures 4c and 5c) of doxorubicin and cultivated under the state of normoxia and hypoxia.
  • FIGS. 4a, 4b and 4c, and 5a, 5b and 5c are photographs of electrophoresis showing the patterns of DNA fragmentation depending on the changes of doxorubicin concentration under the state of normoxia and hypoxia, respectively.
  • M indicates lOObp DNA marker and 1, 2, 3, 4, 5, 6 and 7 represent DNAs extracted from cells at the elapsed time of Ohour, 12hours, 24hours, 30hours, 36hours, 48hours and 72hours after treatment of doxorubicin, respectively.
  • Figures 4a, 4b and 4c it was found that: under the state of normoxia, DNA fragmentation was observed after 72hours with no treatment of doxorubicin, and it was observed earlier, as the concentration of doxorubicin increased.
  • Figures 5a, 5b and 5c have shown that: under the state of hypoxia, DNA fragmentation began to be observed from the elapsed time of 24hours in all cases; and, it was further observed to the elapsed time of 30hours with no treatment of doxorubicin, to the elapsed time of 72hours with O.l ⁇ g/mL treatment, to the elapsed time of 48hours with l ⁇ g/mL treatment, respectively, and then, it was not observed any more. Therefore, it could be concluded that doxorubicin can induce apoptosis under the state of normoxia, while it suppresses apoptosis under the state of hypoxia.
  • Example 2 Effects of other anticancer agents on survival and metabolism of cells under the state of hypoxia
  • anticancer agents such as doxorubicin (Ildong Pharmaceutical Co., Ltd., Korea), epirubicin (Ildong Pharmaceutical Co., Ltd., Korea), mitomycin C (Korea United Pharm. Co., Ltd., Korea), etoposide (Dong-a Pharmaceutical Co., Ltd., Korea) and dactinomycin (Merck & Co., Inc., USA) were used in the experiments.
  • Table 1 shows the effects of anticancer agents acting as topoisomerase inhibitors on the repression of apoptosis. As shown in Table 1 below, under the state of hypoxia, all of the anticancer agents acting as topoisomerase inhibitors, though their effective amounts are different from one another, possessed a biological activity of repressing apoptosis and mitomycin C, an alkylating agent, possessed the same activity, while the other anticancer agents possessed little activities. Therefore, it was clearly demonstrated that anticancer agents acting as topoisomerase inhibitors repress apoptosis under the state of hypoxia.
  • FIGS. 6a and 6b are the graphs showing the survival rates of cells depending on the changes of pimonidazole concentration under the state of normoxia and hypoxia, respectively.
  • FIGS. 7a and 7b are the graphs showing the glucose concentrations of cell culture depending on the changes of pimonidazole concentration under the state of normoxia and hypoxia, respectively.
  • Figures 8a and 8b are the graphs showing the lactic acid concentrations of cell culture depending on the changes of pimonidazole concentration under the state of normoxia and hypoxia, respectively.
  • Figures 8a and 8b it was observed that: under the state of normoxia, lOO ⁇ g/mL and less pimonidazole had little effect on the variation of lactic acid concentration, similarly as the above results of the survival rate of cells and the concentration of glucose; under the state of hypoxia, lOO ⁇ g/mL and more pimonidazole only had an effect on the variation of lactic acid concentration, similarly as the above results of glucose concentration.
  • Example 4 Effects of pimonidazole and doxorubicin on survival and metabolism of cells
  • Figures 9a and 9b are the graphs showing the survival rates of cells depending on the changes of pimonidazole concentration under the state of normoxia and hypoxia, respectively.
  • the results of treating both pimonidazole and doxorubicin were very similar to those of treating only doxorubicin under the state of normoxia, while the former showed more rapid decrease of cell survival rate than the latter. Accordingly, these results indicated that: treatment of both lOO ⁇ g/mL of pimonidazole and doxorubicin whose concentration is within the range for maintaining cell survival under the state of hypoxia has no significant effect on cell survival under the state of normoxia, while it induces cell death under the state of hypoxia.
  • FIGS 10a and 10b are the graphs showing the glucose concentrations of cell culture depending on the changes of pimonidazole and doxorubicin concentrations under the state of normoxia and hypoxia, respectively, and Figures 11a and lib, graphs showing the lactose concentration of cell culture depending on the changes of pimonidazole and doxorubicin concentrations under the state of normoxia and hypoxia, respectively.
  • each DNA was extracted from cells treated with lOO ⁇ g/mL of pimonidazole ( see : Figures 12a and 13a), O.l ⁇ g/mL of doxorubicin and lOO ⁇ g/mL of pimonidazole (see: Figures 12b and 13b), and I ⁇ g/mL of doxorubicin and lOO ⁇ g/mL of pimonidazole ( see : Figures 12c and 13c) , respectively, and then DNA fragmentation was examined in a similar manner as in Example 1-3.
  • Figures 12a, 12b and 12c, and 13a, 13b and 13c are photographs showing DNA fragmentation patterns depending on the changes of pimonidazole and doxorubicin concentrations under the state of normoxia and hypoxia, respectively. As shown in Figures 12a, 12b, 12c, 13a, 13b, and 13c, only doxorubicin had an effect under the state of normoxia, while only pimonidazole had an effect under the state of hypoxia.
  • Example 5 Effects of doxorubicin and pimonidazole depending on oxygen concentration
  • Table 2 shows the survival rates of cells with symbols of ®, O, ⁇ , ⁇ , ⁇ x and x in a descending order, at various concentrations of oxygen, doxorubicin and pimonidazole.
  • O.l ⁇ g/mL of doxorubicin had stronger activity of maintaining cell survival than that of control only under the condition of less than 3% oxygen
  • l ⁇ g/mL of doxorubicin did only under the condition of 1% oxygen.
  • pimonidazole treatment only pimonidazole had stronger activity of inducing cell death under the condition of less than 10% oxygen, than that of control.
  • Example 6 Effects of co-treatment of nitroimidazole and other anticancer agents
  • Nitroimidazole compounds used herein include metronidazole (Keunhwa Chem. Co., Korea), ornidazole (Keunhwa Chem. Co., Korea), etanidazole (Sigma Chem. Co., USA), tinidazole (Sigma Chem. Co., USA), dimetridazole (Sigma Chem.
  • Table 3 shows the effects of nitroimidazole with co-treatment of other anticancer agents, where each numeral indicates the concentration ( ⁇ g/mL) of a nitroimidazole compound sufficient for inhibiting the activity of an anticancer agent for maintaining cell survival, each value in ⁇ ( ) ' indicates the time of showing the activity at the above concentrations of nitroimidazole, each value after V indicates the concentration of an anticancer agent, at which it has the strongest activity of maintaining cell survival, and x' indicates almost no effect.
  • lOO ⁇ g/mL of pimonidazole if co-treated with other anticancer agents besides doxorubicin, which maintain cell survival under the state of hypoxia, can lead all cells to death within 24 hours.
  • misonidazole and etanidazole possessed similar activity at the high concentration of lOOO ⁇ g/mL, and lOOO ⁇ g/mL of ornidazole did the same if co-treated only with doxorubicin, camptothesin or dactinomycin.
  • all of nitroimidazole compounds except the aboves had no activity unless they were co-treated with dactinomycin.
  • the present invention provides an anticancer agent comprising active ingredients of nitroimidazole compound such as pimonidazole, misonidazole, etanidazole and ornidazole, and a topoisomerase inhibitor such as doxorubicin, mitomycin C, camptothecin, novobiocin, epirubicin, dactinomycin and etoposide, and their pharmaceutically acceptable carriers.
  • the anticancer agent induces cell death by the activity of topoisomerase inhibitor under the state of normoxia as well as by the activity of nitroimidazole compound under the state of hypoxia. Accordingly, the anticancer agent can be practically applied for the treatment of almost all kinds of cancer, inter alia , solid cancer creating the state of hypoxia regardless of oxygen condition.

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Abstract

La présente invention concerne un agent anticancéreux renfermant, comme ingrédients actifs, un composé nitro-imidazole, tels que du pimonidazole, du misonidazole, de l'étanidazole et l'ornidazole et un inhibiteur de la topoisomérase, tel que la doxorubicine, la mitomycine C, la camptothécine, la novobiocine, l'épirubicine, la dactinomycine et l'étoposide, et leurs excipients de qualité pharmaceutique. Cet agent anticancéreux permet d'induire la mort cellulaire grâce à l'activité de l'inhibiteur de la topoisomérase dans un état de normoxie et de l'activité du composé nitro-imidazole dans un état d'hypoxie. Par conséquent, l'agent anticancéreux peut être utilisé pour le traitement de la plupart des cancers et, notamment, du cancer solide induisant un état d'hypoxie, quelles que soient les conditions d'oxygénation.
PCT/KR2003/000276 2002-02-07 2003-02-07 Agent anticancereux renfermant du nitro-imidazole et un inhibiteur de la topoisomerase comme ingredients actifs Ceased WO2003066052A1 (fr)

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KR1020020007185A KR20030067275A (ko) 2002-02-07 2002-02-07 니트로이미다졸 및 위상 이성질화 효소 저해제를유효성분으로 포함하는 항암제
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8003625B2 (en) 2005-06-29 2011-08-23 Threshold Pharmaceuticals, Inc. Phosphoramidate alkylator prodrugs
WO2012003562A1 (fr) * 2010-07-07 2012-01-12 Universidade Federal De Minas Gerais - Ufmg Compositions pharmaceutiques antinéoplasiques contenant des nitroimidazols substitués
US8299088B2 (en) 2003-03-28 2012-10-30 Threshold Pharmaceuticals, Inc. Compositions and methods for treating cancer
US8552048B2 (en) 2006-12-26 2013-10-08 Threshold Pharmaceuticals, Inc. Phosphoramidate alkylator prodrugs for the treatment of cancer
CN104546833A (zh) * 2015-02-09 2015-04-29 江苏澳格姆生物科技有限公司 奥硝唑在制备抑制肿瘤细胞转移和扩散的药物中的应用
WO2019023621A1 (fr) * 2017-07-28 2019-01-31 Yale University Médicaments anticancéreux et leurs procédés de fabrication et d'utilisation

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ELIAS ANTHONY D. ET AL.: "Dose escalation of the hypoxic cell sensitizer etanidazole combined with ifosfamide, carboplatin, etoposide and autologous hematopoietic stem cell support", CLIN. CANCER RES., vol. 4, no. 6, 1998, pages 1443 - 1449 *
RAUTH A.M. ET AL.: "Bioreductive therapies: an overview of drugs and their mechanisms of action", INT. J. RADIAT. ONCOL. BIOL. PHYS., vol. 42, no. 4, 1998, pages 755 - 762, XP002131257, DOI: doi:10.1016/S0360-3016(98)00302-2 *
URTASUN RAUL C. ET AL.: "Intervention with the hypoxic tumor cell sensitizer etanidazole in the combined modality treatment of limited stage small-cell lung cancer. A one-institution study", INT. J. RADIAT. ONCOL. BIOL. PHYS., vol. 40, no. 2, 1998, pages 337 - 342 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8299088B2 (en) 2003-03-28 2012-10-30 Threshold Pharmaceuticals, Inc. Compositions and methods for treating cancer
US8003625B2 (en) 2005-06-29 2011-08-23 Threshold Pharmaceuticals, Inc. Phosphoramidate alkylator prodrugs
US8507464B2 (en) 2005-06-29 2013-08-13 Threshold Pharmaceuticals, Inc. Phosphoramidate alkylator prodrugs
US8664204B2 (en) 2005-06-29 2014-03-04 Threshold Pharmaceuticals, Inc. Phosphoramidate alkylator prodrugs
US9226932B2 (en) 2005-06-29 2016-01-05 Threshold Pharmaceuticals, Inc. Phosphoramidate alkylator prodrugs
US8552048B2 (en) 2006-12-26 2013-10-08 Threshold Pharmaceuticals, Inc. Phosphoramidate alkylator prodrugs for the treatment of cancer
WO2012003562A1 (fr) * 2010-07-07 2012-01-12 Universidade Federal De Minas Gerais - Ufmg Compositions pharmaceutiques antinéoplasiques contenant des nitroimidazols substitués
CN104546833A (zh) * 2015-02-09 2015-04-29 江苏澳格姆生物科技有限公司 奥硝唑在制备抑制肿瘤细胞转移和扩散的药物中的应用
WO2019023621A1 (fr) * 2017-07-28 2019-01-31 Yale University Médicaments anticancéreux et leurs procédés de fabrication et d'utilisation

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AU2003208037A1 (en) 2003-09-02

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